A Phase I and Randomized Phase II Multicenter Study of Cabozantinib (XL184) Plus Docetaxel and Prednisone in Metastatic Castrate Resistant Prostate Cancer
A Phase I and Randomized Phase II Multicenter Study of Cabozantinib (XL184) Plus Docetaxel and Prednisone in Metastatic Castrate Resistant Prostate Cancer
Background:
- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. However, studies have shown that prostate tumors respond to it. Docetaxel and prednisone are standard treatments for advanced prostate cancer. Researchers want to see if adding cabozantinib to these two drugs can be a safe and effective treatment for this type of cancer.
Objectives:
- To test the safety and effectiveness of cabozantinib with standard treatments for advanced prostate cancer.
Eligibility:
- Individuals at least 18 years of age who have advanced prostate cancer that has not responded to standard treatments.
Design:
Background:
Objectives:
Eligibility:
Design:
Progression must be evidenced and documented by any of the following parameters:
The use of androgen receptor inhibitors is not required prior to study entry. For those patients receiving an anti-androgen agent (flutamide, bicalutamide, or nilutamide), for at least 6 consecutive months immediately prior to study entry, and are entering the trial due to a rise in PSA, they must demonstrate a continued rise in PSA within 4 weeks after stopping flutamide and within 6 weeks after stopping bicalutamide or nilutamide. Flutamide, nilutamide and bicalutamide disease progression requirements only apply to patients who have been on these drugs for at least the prior 6 months.
Histopathological confirmation of prostate cancer by the Laboratory of Pathology of the National Cancer Institute (NCI) Pathology Department of the Walter Reed National Military Medical Center or YALE is required prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled if the patient has a clinical course that is consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. All efforts should be made to have the material forwarded to the research team for use in correlative studies in cases where original tissue blocks or archival biopsy material is available.
Patients must have metastatic disease, defined as at least one lesion on bone scan or at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
Patients must have a performance status of 0 to 2 according to the ECOG criteria.
Patients must have adequate bone marrow, hepatic, and renal function with:
OR
creatinine clearance of greater than or equal to 50 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal by 24 hour urine.
urine protein/urine creatinine ratio (UPCR) less than or equal to 1
EXCLUSION CRITERIA:
The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment
The subject is unable to swallow tablets
The subject has tumor invading (or there is concern for invasion of) major blood vessel
The subject has active brain metastases or epidural disease Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain scans are not required to confirm eligibility.
The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (less than or equal to 81 milligrams per day), low-dose warfarin (less than or equal to1 milligrams per day), and prophylactic low molecular weight heparin (LMWH) are permitted.
The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) greater than 500 milliseconds within 28 days before initiation of protocol therapy. Note: if initial QTcF is found to be greater than 500 milliseconds, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is less than or equal to 500 milliseconds, the subject meets eligibility in this regard.
Patients with contraindication to steroid use
Prior treatment with cabozantinib
The patient has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.
The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment with the exception of patients receiving prior abiraterone or ketoconazole. For patients receiving prior abiraterone or ketoconazole, they must discontinue the medication within 5 half lives of the compound before the first dose of study treatment in order to participate in this study. Note: Subjects with prostate cancer currently receiving LHRH or GnRH agonists must be maintained on these agents.
The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
The subject has received radiation therapy:
The subject has received radionuclide treatment within 6 weeks prior to the first dose of the study treatment
The subject has not recovered to baseline or CTCAE less than or equal to Grade 1 from toxicity due to all prior therapies, including surgery, except alopecia and other non-clinically significant AEs.
The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test results at screening greater than or equal 1.3 times the laboratory ULN within 7 days before the first dose of study treatment
The subject has experienced any of the following:
The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
Cardiovascular disorders including
Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
Concurrent uncontrolled hypertension defined as sustained BP greater than 140 millimeters of mercury systolic, or greater than 90 millimeters of mercury diastolic despite optimal antihypertensive treatment (BP must be controlled at screening)
Any history of congenital long QT syndrome
Any of the following within 6 months before the first dose of study treatment:
unstable angina pectoris
clinically-significant cardiac arrhythmias
stroke (including TIA, or other ischemic event)
myocardial infarction
Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
Any of the following within 28 days before the first dose of study treatment
intra-abdominal tumor/metastases invading GI mucosa
active peptic ulcer disease
inflammatory bowel disease (including ulcerative colitis and Crohns disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
Any of the following within 6 months before the first dose of study treatment:
Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus.
Other clinically significant disorders such as:
active infection requiring intravenous treatment within 10 days of starting protocol
serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
history of organ transplant
concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
history of major surgery as follows:
In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery
Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-thecounter medicine or herbal product.